Mastery of Emotions: Joseph LeDoux and the Discovery of Fear

In Scientific American Mind, Feb/March 2006:

One of the biggest fears Joseph LeDoux had when he was young — he’s 55 now, and a leading neuroscientist specializing in the study of fear — was of getting stuck in his hometown. Eunice, Louisiana, population 11,499, sits among the creeks and rice fields of southwestern Louisiana, and a revival of the town’s Cajun country roots gives it a certain charm today. An old theater downtown hosts the weekly “Rendezvous des Cajun” radio show, a yipping, Frenchified version of Prairie Home Companion, only with dancing, which you can enjoy for a mere $5 (small children free), and you can’t swing a ‘possum without hitting a good gumbo place. But when LeDoux was coming of age in the 1960s, he found the place too sleepy. He did some radio disc jockeying in high school, and the era’s music, along with his own inquisitiveness, drew his attention to the wider world. His parents, however — his father was a butcher, and Joseph did his first neural explorations digging through cow brains to extract the bullets that had dispatched them — envisioned him as a leading local businessman. His parents conditioned college tuition payments on his studying business – and no further away than Baton Rouge, 80 miles east, where LeDoux dutifully enrolled at Louisiana State University. 

“I didn’t much care for business,” LeDoux told me last fall in his NYU office. His gentle, amiable voice carries the slightest hint of Cajun. It was a bright day, and the Empire State Building gleamed a couple miles north beyond his windows. “I studied marketing, and as I went along, the thing that interested me most about it was why people bought stuff they didn’t really need.” LeDoux’s interest in manufactured desire led him to a course on learning and motivation with LSU psychologist Robert Thompson. LeDoux and Thompson hit it off, and Thompson urged LeDoux to apply to graduate school in neuroscience. Of thirty programs LeDoux applied to, only one, SUNY Stonybrook, accepted him, and that, LeDoux says, only because Thompson convinced his friend Michael Gazzaniga, who then headed Stonybrook’s neuroscience program, to take a chance. 

Gazzaniga and LeDoux would both go on to stellar careers. Gazzaniga, a prime leader of cognitive neuroscience and editor of MIT Press’s authoritative The Cognitive Neurosciences, this winter moved from Dartmouth, where since 1996 he headed the Center for Cognitive Neuroscience, to direct the new Sage Center for the Study of the Mind at the University of California at Santa Barbara. His protégé, meanwhile, has more than justified Gazzaniga’s faith in taking him on. Over the last two decades, LeDoux has led a broad inquiry that has turned an area that most neuroscientists were loathe to plumb — the neurobiology of emotion, and particularly of fear — into one of neuroscience’s most revealing disciplines. With remarkable tenacity and creativity he has used simple fear conditioning in the rat to identify the neural pathways and processes through which rats acquire, act on, and sometimes extinguish their fears. Because most of these neural networks and dynamics exist and operate similarly in humans, his findings have vastly expanded our understanding of how emotions affect our thoughts, moods, motivations, memory, and behavior. His findings are also aiding development of drugs and other treatments for the many millions who suffer mental disorders caused or aggravated by anxiety. 

“When he started,” Gazzaniga recalls, “he was a long-hair ponytail, and maybe some wouldn’t have thought him impressive. But there are people who walk in and you see right away they have it. Joe was one.” Of the recent explosion in the biology of fear, says Gazzaniga, “Joe has been the driving force.” 


From a Simple Start, Many Paths 

Behind many a long, productive inquiry stands a simple method. For LeDoux, that method has been the conditioned response: By associating an initially neutral stimulus, such as a tone or a light, with something more consequential, such as an electric shock or a meal, you condition an animal to respond to the neutral stimulus — now the “conditioned stimulus” — as if it were the more consequential stimulus.

Such conditioning has been a staple of mind research since Pavlov published his dog studies in 1903. LeDoux, like many researchers, has used rats, and his basic tool has been the pairing of a tone with a mild electric footshock to instill a fear that can be explored neurally and behaviorally. He puts a rat in a cage, sounds a tone, then sends a mild shock through the metal cage floor. After a few repetitions, the mere sound of the tone, without the shock, will make the rat “freeze” in fear – become suddenly still, with an arched back and accelerated pulse. LeDoux’s genius, first as a grad student with Gazzaniga, then as a post-doc and professor at Cornell from 1977 to 1989, and since then at NYU, has been to use this simple conditioned response to analyze ever more closely how the rat’s brain, and particularly the amygdala — the almond-shaped structure near the center of the brain, long considered the seat of emotions — creates associations of tone and shock and incorporates that learning into future behavior. 

He started, as pioneers do, by finding the most basic pathways. His first paper, written when he was a post-doc in 1985, found that the primary neural pathway for emotional auditory memories — that is, tones or other sounds that instill fear — runs directly from from the sensory thalamus (the brain’s receiving room for most sensory information) to the amygdala. This is a very quick path — 5 milliseconds — that bypasses conscious awareness but puts the body on alert. LeDoux then isolated a second pathway, slower and less direct but more information-rich, that goes from the thalamus to the auditory cortex — part of the brain’s “thinking” area, which helps further define and interpret the sound — before continuing on to the amygdala. To the general instant alarm created by the first pathway that goes straight from ear to amygdala, this longer circuit adds context from memories, other elements of cognitive awareness, and more complex learned responses. 

Tinkering with those paths revealed some interesting things. LeDoux found that if he cut the first, fast pathway, a rat could not develop a new conditioned response; you could pair a tone with a shock all you wanted, but the rat wouldn’t learn to fear the tone. But if LeDoux took a conditioned rat and destroyed the second, “smart” pathway (the one through auditory cortex), the rat would become functionally deaf — unresponsive to virtually all sound —yet he would still freeze in response to the sound of a conditioned tone. Though the rat was aware of no sound — it didn't "hear" the tone — his ear passed the tone to his amygdala so that the amygdala sounded the general alarm. If you did this to a person, the person would be functionally deaf but would still jump if a door slammed behind him. The amygdala’s most basic reactions, then, occur independent of awareness. 

The second, slower loop, then, adds all the information that lets us identify and react appropriately to an alarm (or any other input). In the rat, for instance, this cortical pathway is crucial to what LeDoux calls emotional actions (rather than reactions) designed to avoid or escape the tone. A normal, conditioned rat, for instance, can be slowly be taught to walk across a cage to a certain spot to stop the feared tone. But a rat without the second, smart pathway to the amygdala cannot learn that behavior. The slower, cortical pathway allows responses more sophisticated than freezing. Thus it’s the simpler pathway that makes you jump when the smoke alarm goes off, the longer, cortical pathway takes over to send you out the door or across the room to turn it off. 

Along with identifying these pathways between amygdala, thalamus, cortex, and other areas, LeDoux has broken down the amygdala itself — the center of the fear network — into different functional regions (the lateral, central, and dorsal nuclei) that play different roles in communicating with other brain areas. The most vital of these other areas are the hippocampus (a sort of directory for memory storage), the prefrontal cortex (which incorporates sensory information into the “thinking” brain), and the hypothalamus, which in tense situations recruits the adrenal and pituitary glands to mobilize the body for response. By knocking out or isolating the various pathways among these areas, LeDoux found that the amygdala plays a crucial role not just in acquiring emotionally laden memories but in consolidating them. Startle someone a few seconds after she’s seen a picture of a threatening face, for instance (while she’s consolidating that memory), and you’ll strengthen her memory of the face. Likewise you’ll strengthen the memory if you startle her when she’s recalling that threatening face. Jolting the amygdala into activity tends to strengthen and color not only memories formed during the stimulation, but those recalled. 

Beyond the Basics 

LeDoux’s earliest studies, then, helped establish the surprisingly complex dynamics behind our simplest fear reactions. His subsequent work, and that of others building on his since the early 1990s, has shown the amygdala to figure heavily in the more complex human spheres of social relations, attention, and even perception. The amygdala, it turns out, works at a level that, if “lower” and less aware than our thinking cortexes, is still “higher” than basic perception. As CalTech’s Ralph Adolphs, an expert on emotion, memory, and social cognition, has put it, the amygdala “pervades the organization of thought and behavior at all levels.” 

Socially, for instance, patients with amygdala damage often overlook emotionally laden stimuli. They tend to miss fear expressions altogether and find all faces more trustworthy and approachable than the rest of us do. They also view pictures of landscapes more positively. They’re slightly, happily naïve. In that they resemble monkeys with amygdala lesions, which have been shown to approach other monkeys more quickly and openly than normal monkeys do. In the monkey study this elicited friendly reception. In human relations it can spell trouble. 

The amygdala’s recruitment of memory, knowledge, and association also appear crucial to deciding, amid all the din coming at us all the time, what matters. This is suggested not only by LeDoux’s work with rats but by recent imaging, behavioral, and lesion studies on humans. Growing evidence indicates that the amygdala enhances and directs our perception and attention regarding emotions other than fear — pleasure or disgust, for instance — by calling to attention key parts of our brains and making them more responsive and “stickier” in forming memories and associations. By attuning the brain to all manner of threats and pleasures — not just the snake on the path but the scowl on your boss’s face and the smile on your child’s — the amygdala helps give emotional significance to a wide range of experience. To the age-old question, “What gives life meaning?", it appears a big part of the answer is spelled a-m-y-g-d-a-l-a. 

One implication of this is that the amygdala may play a leading role in establishing what consciousness researchers call “salience” – that is, in choosing which stimuli we prioritize, and therefore what we’re conscious of. This Oz-behind-the-curtain power has LeDoux convinced that the amygdala and its subcortical allies, rather than our consciousness, defines who we are. “Consciousness may get all the focus,” LeDoux once told me. “But consciousness is a small part of what the brain does, and it's a slave to everything that works beneath it. I don’t think that’s what produces our selves.” Rather, says LeDoux, our identities arise from the singular arrays of learned fears, desires, associations, expectations that are ingrained most fundamentally and broadly in our unconscious. As he put it in his book The Synaptic Self, “You are your synapses.” 


Attacking Anxiety 

We don’t need metaphysics to grant the amygdala importance. As LeDoux notes, fear and its more persistent cousin anxiety “are the root of almost all our emotional disorders.” Over half of mental-health visits in the United States each year are for anxiety or anxiety-related conditions running from post-traumatic stress disorder (PTSD) and generalized anxiety disorder to obsessive-compulsive disorder, schizophrenia, and depression. Anxiety either drives these conditions or makes them dangerously unbearable. 

Anxiety, of course, differs from fear, being brought on not by immediate stimulus but by our worries or memories about stimuli real or imagined. From a LeDouxian perspective, one can view anxiety as a mismatch in traffic capacity between pathways lying between the amygdala and the various centers of thought, imagination, and planning that humans have so recently developed. LeDoux and others have found far more neural pathways running from the amygdala to the cortex, for instance, than from cortex to amygdala. This may be why our anxieties often control our thoughts, while our thoughts have trouble quelling our anxieties. Our imagination easily amplifies and feeds the fears coming from the amygdala and hippocampus — we readily worry about what might be or what might have been — but we can’t send enough controls back from cortex to amygdala and hippocampus to dampen the resulting anxiety. That’s why we can seldom calm ourselves by telling ourselves to be calm. 

LeDoux hopes that we’ll soon learn enough about anxiety’s neural circuits to correct truly debilitating instances of this imbalance, using drugs or other therapies that tweak the appropriate neural circuits. Take, for instance, the neural dynamics of extinction — the apparent erasure of a learned fear. We’ve known for decades that fears are extinguished not because they fade, but because new, less threatening associations take their place. If a fear-conditioned rat hears the threatening tone repeatedly without experiencing pain, a neutral association slowly replaces the fearful one. Likewise, if you hear often enough the once-lacerating song you long ago enjoyed with your ex-lover, the song loses its bite.

Researchers have recently found that this process relies on a calming of the amygdala via the medial prefrontal cortex. If they can identify the particular neural, molecular, or genetic switches for this process, they might be able to design drugs or other treatments that ease the pain of memories or even erase memories underlying, say, PTSD. “Some people are uncomfortable with that idea,” LeDoux notes, referring to concerns some ethicists have expressed that such treatments could be used in Big-Brother fashion to control people’s minds. “But they never seem to be people with PTSD.

"Few object to the idea of improving our memories,” he says, giving a nod at the coffee I’m drinking to improve my own attention, cognition, and short-term memory. “I don’t see a big difference between improving your or your aunt’s memory and removing a memory that someone doesn’t want.” 

As the study of emotions, memory, and their implications expands, LeDoux seems certain to remain in its forefront. He possesses enormous energy and creativity, and as the director of the Center for the Study of Fear and Anxiety, which forms collaborative links among leading researchers at NYU, Rockefeller University, Mt. Sinai School of Medicine in New York, and Cornell Medical School, he is part of a network offering stunning resources and intellect. Lately he’s been investigating reconsolidation — the controversial but exciting notion that memories are made labile when we recall them, getting updated or altered by new information or associations we’ve learned acquiring the memory. Growing evidence supports this fanciful-sounding notion. We’ve long known, for instance, that building the synapses that hold long-term memories requires protein synthesis; LeDoux and other researchers recently found that if you disrupt protein synthesis while a memory is recalled, a memory that would otherwise be lasting can be made fleeting. 

Some fears, of course, are universal. Even a rat whose ancestors forty generations deep were lab animals that never saw a cat will freeze, terrified, if they smell a cat's scent. And people fear the dark, the rattlesnake’s rattle, and not just their own deaths but those of the people they love. These latter, seemingly elemental fears, of course, rise partly from the imagination and foresight that can make us neurotic or phobic. But LeDoux, who has suffered his own share of shocks and grief, feels these fears affirm the things we live for. 

“The backside of every positive emotion,” he says, “is the fear you’ll lose what makes you happy. Not only do you love your wife, even after thirty years, but you’re also afraid of what life would be like without her. How much should you trust your positive emotions? How do you focus on and enjoy them and not give in to the fear? These are things we all wrestle with. I’m afraid fear is terribly basic.”